Randomized Phase II Trial of Immunotherapy-Based Total Neoadjuvant Therapy for Proficient Mismatch Repair or Microsatellite Stable Locally Advanced Rectal Cancer (TORCH).

PURPOSE: To assess whether the integration of PD-1 inhibitor with total neoadjuvant therapy (iTNT) can lead to an improvement in complete responses (CRs) and favors a watch-and-wait (WW) strategy in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). PATIENTS AND METHODS: We conducted a prospective, multicenter, randomized, open-label, phase II trial using a pick-the-winner design. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly assigned to group A for short-course radiotherapy (SCRT) followed by six cycles of consolidation immunochemotherapy with capecitabine and oxaliplatin and toripalimab or to group B for two cycles of induction immunochemotherapy followed by SCRT and the rest four doses. Either total mesorectal excision or WW was applied on the basis of tumor response. The primary end point was CR which included pathological CR (pCR) after surgery and clinical CR (cCR) if WW was applicable, with hypothesis of an increased CR of 40% after iTNT compared with historical data of 25% after conventional TNT. RESULTS: Of the 130 patients enrolled, 121 pMMR/MSS patients were evaluable (62 in group A and 59 in group B). At a median follow-up of 19 months, CR was achieved at 56.5% in group A and 54.2% in group B. Both groups fulfilled the predefined statistical hypothesis (P < .001). Both groups reported a pCR rate of 50%. Respectively, 15 patients in each group underwent WW and remained disease free. The most frequent grade 3 to 4 toxicities were thrombocytopenia and neutropenia. Patients in group A had higher rate of cCR (43.5% v 35.6%) at restaging and lower rate of grade 3 to 4 thrombocytopenia (24.2% v 33.9%) during neoadjuvant treatment. CONCLUSION: The iTNT regimens remarkably improved CR rates in pMMR/MSS LARC compared with historical benchmark with acceptable toxicity. Up-front SCRT followed by immunochemotherapy was selected for future definitive study.

Effects of the antitumor drugs adagrasib and asciminib on apixaban metabolism in vitro and in vivo.

Apixaban is an oral anticoagulant that directly inhibits the target Factor Xa (FXa). In this study, we focused on the in vivo and in vitro effects of adagrasib and asciminib on apixaban metabolism, to discover potential drug-drug interactions (DDI) and explore their inhibitory mechanisms. The levels of apixaban and its metabolite, O-desmethyl-apixaban (M2), were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In vitro evaluation, the maximum half inhibitory concentration (IC50) of adagrasib in rat liver microsomes (RLM) and human liver microsomes (HLM) against apixaban was 7.99 µM and 117.40 µM, respectively. The IC50 value of asciminib against apixaban in RLM and HLM was 4.28 µM and 18.42 µM, respectively. The results of the analysis on inhibition mechanisms showed that adagrasib inhibited the metabolism of apixaban through a non-competitive mechanism, while asciminib inhibited the metabolism of apixaban through a mixed mechanism. Moreover, the interaction of apixaban with adagrasib and asciminib in Sprague-Dawley (SD) rats was also investigated. It was found that the pharmacokinetic characteristics of apixaban were significantly changed when combined with these two antitumor drugs, where AUC(0-t), AUC(0-∞), t1/2, Tmax, and Cmax were increased, while CLz/F was significantly decreased. But both drugs did not appear to affect the metabolism of M2 in a significant way. Consistent results from in vitro and in vivo demonstrated that both adagrasib and asciminib inhibited the metabolism of apixaban. It provided reference data for the future clinical individualization of apixaban.

Exploring the Cellular Impact of Size-Segregated Cigarette Aerosols: Insights into Indoor Particulate Matter Toxicity and Potential Therapeutic Interventions.

Exposure to anthropogenic aerosols has been associated with a variety of adverse health effects, increased morbidity, and premature death. Although cigarette smoke poses one of the most significant public health threats, the cellular toxicity of particulate matter contained in cigarette smoke has not been systematically interrogated in a size-segregated manner. In this study, we employed a refined particle size classification to collect cigarette aerosols, enabling a comprehensive assessment and comparison of the impacts exerted by cigarette aerosol extract (CAE) on SH-SY5Y, HEK293T, and A549 cells. Exposure to CAE reduced cell viability in a dose-dependent manner, with organic components having a greater impact and SH-SY5Y cells displaying lower tolerance compared to HEK293T and A549 cells. Moreover, CAE was found to cause increased oxidative stress, mitochondrial dysfunction, and increased levels of apoptosis, pyroptosis, and autophagy, leading to increased cell death. Furthermore, we found that rutin, a phytocompound with antioxidant potential, could reduce intracellular reactive oxygen species and protect against CAE-triggered cell death. These findings underscore the therapeutic potential of antioxidant drugs in mitigating the adverse effects of cigarette aerosol exposure for better public health outcomes.

Influence of Cigarette Aerosol in Alpha-Synuclein Oligomerization and Cell Viability in SH-SY5Y: Implications for Parkinson's Disease.

Although cigarette aerosol exposure is associated with various adverse health issues, its impact on Parkinson's disease (PD) remains elusive. Here, we investigated the effect of cigarette aerosol extract (CAE) on SH-SY5Y cells for the first time, both with and without α-synuclein (α-Syn) overexpression. We found that α-Syn aggravates CAE-induced cell death, oxidative stress, and mitochondrial dysfunction. Fluorescence cross-correlation spectroscopy (FCCS) revealed a dual distribution of α-Syn within the cells, with homogeneous regions indicative of monomeric α-Syn and punctated regions, suggesting the formation of oligomers. Moreover, we observed colocalization of α-Syn oligomers with lysosomes along with a reduction in autophagy activity. These findings suggest that α-Syn overexpression exacerbates CAE-induced intracellular cytotoxicity, mitochondrial dysfunction, and autophagy dysregulation, leading to elevated cell mortality. Our findings provide new insights into the pathogenic mechanisms linking exposure to cigarette aerosols with neurodegenerative diseases.

Optical single-channel cryptosystem based on the non-negative matrix factorization and face biometric in cyan-magenta-yellow-black color space.

In this paper, an optical color single-channel asymmetric cryptosystem based on the non-negative matrix factorization (NMF) and a face biometric in cyan-magenta-yellow-black (CMYK) space is proposed. To the best of our knowledge, this is the first time that NMF has been introduced into optical color image encryption. In the proposed cryptosystem, the color image in CMYK space is first decomposed into four color channels: C, M, Y, and K. By performing NMF operations on the four color channels, the four basic and sparse matrices can be obtained, respectively, which achieves asymmetry and saves computational resources. The four basis matrices can be used as private keys, and the four coefficient matrices are synthesized by the inverse discrete wavelet transform for subsequent encryption. Finally, the synthesized image is encoded with double random phase encoding based on phase truncation (PT). Compared with the existing PT-based cryptosystems, our cryptosystem can improve security against a special attack. In addition, the chaotic random phase mask is generated by a face biometric, which is noncontact and unique. Numerical simulation results are shown to verify the feasibility and robustness of our cryptosystem. Further, the proposed cryptosystem can be extended to encrypt multiple images conveniently.

The impacts of CYP3A4 genetic polymorphism and drug interactions on the metabolism of lurasidone.

The aim of this study was to investigate the impacts of 24 variants of recombinant human CYP3A4 and drug interactions on the metabolism of lurasidone. In vitro, enzymatic reaction incubation system of CYP3A4 was established to determine the kinetic parameters of lurasidone catalyzed by 24 CYP3A4 variants. Then, we constructed rat liver microsomes (RLM) and human liver microsomes (HLM) incubation system to screen potential anti-tumor drugs that could interact with lurasidone and studied its inhibitory mechanism. In vivo, Sprague-Dawley (SD) rats were applied to study the interaction between lurasidone and olmutinib. The concentrations of the analytes were detected by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). As the results, we found that compared with the wild-type CYP3A4, the relative intrinsic clearances vary from 355.77 % in CYP3A4.15 to 14.11 % in CYP3A4.12. A series of drugs were screened based on the incubation system, and compared to without olmutinib, the amount of ID-14283 (the metabolite of lurasidone) in RLM and HLM were reduced to 7.22 % and 7.59 %, and its IC50 were 18.83 ± 1.06 µM and 16.15 ± 0.81 µM, respectively. At the same time, it exerted inhibitory effects both through a mixed mechanism. When co-administration of lurasidone with olmutinib in rats, the AUC(0-t) and AUC(0-∞) of lurasidone were significantly increased by 73.52 % and 69.68 %, respectively, while CLz/F was observably decreased by 43.83 %. In conclusion, CYP3A4 genetic polymorphism and olmutinib can remarkably affect the metabolism of lurasidone.

Glutathione metabolism is conserved in response to excessive copper exposure between mice liver and Aurelia coerulea polyps.

BACKGROUND: Copper (Cu) is a trace element that is engaged in various routine physiological processes. Excessive copper exposure can cause damage to organisms; however, it is unknown if the mechanisms underlying the response to Cu2+ among different species are conserved. METHODS: Aurelia coerulea polyps and mice models were exposed to Cu2+ to assess its effects on survival status and organ damage. Transcriptomic sequencing, BLAST, structural analysis, and real-time quantitative PCR were carried out to analyze the similarities and differences in the molecular composition and response mechanisms between two species when exposed to Cu2+. RESULTS: Excessive Cu2+ exposure led to toxic effects on both A. coerulea polyps and mice. The polyps were injured at a Cu2+ concentration of 3.0 mg L-1. In the mice, increasing Cu2+ concentrations were correlated with, the degree of liver damage, which manifested as hepatocyte apoptosis. In the 300 mg L-1 Cu2+ group of mice, livers cell death was primarily triggered by the phagosome and Toll-like signaling pathways. We found the glutathione metabolism was significantly altered in response to copper stress in both A. coerulea polyps and mice. Moreover, the similarity of gene sequences enriched at the two same sites in this pathway was as high as 41.05 %-49.82 % and 43.61 %-45.99 % respectively. Among them, there was a conservative region in the structure of A. coerulea polyps GSTK1 and mice Gsta2, but the overall difference is large. CONCLUSION: Glutathione metabolism is a conserved copper response mechanism in evolutionary distant organisms such as A. coerulea polyps and mice, although mammals have a more complex regulatory network when it comes to copper-induced cell death.

An environmentally sensitive molecular rotor as a NIR fluorescent probe for the detection of islet amyloid polypeptide.

The deposits of human islet amyloid polypeptide (IAPP), also called amylin, in the pancreas have been postulated to be a factor of pancreatic ß-cell dysfunction and is one of the common pathological hallmarks of type II diabetes mellitus (T2DM). Therefore, it is imperative to gain an in-depth understanding of the formation of these aggregates. In this study, we demonstrate a rationally-designed strategy of an environmentally sensitive near-infrared (NIR) molecular rotor utilizing thioflavin T (ThT) as a scaffold for IAPP deposits. We extended the π delocalized system not only to improve the viscosity sensitivity but also to prolong the emission wavelength to the NIR region. A naphthalene moiety was also introduced to adjust the sensitivity of our designed probes to differentiate the binding microenvironment polarity of different targeted proteins. As a result, a novel NIR fluorogenic probe toward IAPP aggregates, namely AmySP-4-Nap-Ene, was first developed. When attached to different protein aggregates, this probe exhibited distinct fluorescence emission profiles. In a comparison with ThT, the fluorescence emission of non-ionic AmySP-4-Nap-Ene exhibits a significant difference between the presence of non-fibrillar and fibrillar IAPP and displays a higher binding affinity toward IAPP fibrils. Further, the AmySP-4-Nap-Ene can be utilized to monitor IAPP accumulating process and image fibrils both in vitro and in living cells.

Identification of noninvasive diagnostic biomarkers for ectopic pregnancy using data-independent acquisition (DIA)proteomics: a pilot study.

At present, the diagnosis of ectopic pregnancy mainly depends on transvaginal ultrasound and ß-hCG. However, these methods may delay diagnosis and treatment time. Therefore, we aimed to screen for serological molecular markers for the early diagnosis of ectopic pregnancy (EP).Using data-independent acquisition (DIA)proteomics, the differential proteins in serum were selected between the intrauterine pregnancy (IP) and EP groups. Then, the expression levels of these differential proteins were measured by enzyme-linked immunosorbent assay. The diagnostic value of the serum biomarkers was evaluated by receiver operating characteristic curve analysis.GSTO1, ECM-1 and ß-hCG showed significant differences between the EP and IP groups (P < 0.05). The combination of GSTO1/ECM-1/ß-hCG had an area under the curve of 0.93 (95% CI 0.88-0.99), a sensitivity of 88.89% (95% CI 73.94-96.89) and a specificity of 86.11% (95% CI 70.50-95.33) with a likelihood ratio of 6.40.The combination of GSTO1/ECM-1/ß-hCG may be developed into a possible approach for the early diagnosis of EP.

Short-Term Outcomes and Clinical Efficacy of Stereotactic Body Radiation Therapy (SBRT) for Oligometastases of Prostate Cancer in China.

Objective: To assess the efficacy and safety of stereotactic body radiation therapy (SBRT) in managing oligometastases of prostate cancer. Moreover, it is the largest-to-date study in China to report the safety and efficacy of SBRT by CyberKnife for oligometastases of prostate cancer. Methods: In this retrospective study, 75 patients with 108 oligometastases were treated by SBRT from May 2012 to February 2021. Among these patients, 43 patients were treated with the intention to control all known metastatic lesions and 32 were treated for palliative care. Patients received regular follow-up evaluations every 3 months. Efficacy was assessed based on local control (LC) rates, biochemical progression-free survival (bPFS), progression-free survival (PFS), and overall survival (OS). Safety was assessed based on clinical adverse events. Results: Median follow-up time was 23.2 months (1.2-106.9 months). The complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 63.0%, 10.2%, 21.3% and 5.6%, respectively. The 6-month, 1-, and 2-year LC rates were 100%, 97.5%, and 96.0% respectively while the 6-month, 1-, and 2-year bPFS rates were 74.6%, 53.3%, and 47.9%, respectively. Additionally, 6-month, 1-, and 2-year PFS rates were 77.5%, 50.8%, and 47.2%, respectively. The 6-month, 1-, and 2-year OS rates were 97.0%, 88.8%, and 87.0%, respectively. For the 15 metastatic castration-resistant prostate cancer (mCRPC) patients with 23 lesions, the 2-year LC rates were 93.8%, while for 60 metastatic hormone-sensitive prostate cancer (mHSPC) patients with 85 lesions, the 2-year LC rates were 96.7%. No predictors of LC were found after univariate analysis. In those not on androgen deprivation therapy (ADT; n = 27), the 2-year freedom from ADT was 44.0%. All of the 24 patients with oligmetastase-induced complications experienced varying degrees of alleviation after SBRT. The treatment was well tolerated. No grade 3 or higher toxicity was observed. Conclusion: SBRT is a safe and effective treatment modality in the management of oligometastases of mHSPC and mCRPC with high LC rates and acceptable toxicity. SBRT could provide a treatment choice for mCRPC, as well as an alternative to delay the start of ADT for mHSPC.

Identification of Cell Subpopulations and Interactive Signaling Pathways From a Single-Cell RNA Sequencing Dataset in Osteosarcoma: A Comprehensive Bioinformatics Analysis.

Osteosarcoma is a type of highly aggressive bone tumor arising from primitive cells of mesenchymal origin in adults and is associated with a high rate of tumor relapse. However, there is an urgent need to clarify the molecular mechanisms underlying osteosarcoma development. The present study performed integrated bioinformatics analysis in a single-cell RNA sequencing dataset and explored the potential interactive signaling pathways associated with osteosarcoma development. Single-cell transcriptomic analysis of osteosarcoma tissues was performed by using the Seurat R package, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of differentially expressed genes was performed by using the clusterProfiler R package, and the cell-cell interaction analysis was performed by using the CellPhoneDB package. Our results showed that 11 clustered cell types were identified across 11 osteosarcoma tissues, with cell types including "osteoblastic", "myeloid", "osteoblastic_proli", "osteoclast", and "tumor-infiltrating lymphocytes (TILs)" as the main types. The DEGs between different cell types from primary, metastatic, and recurrent osteosarcomas were mainly enriched in the GO terms including "negative regulation of hydrolase activity", "regulation of peptidase activity", "regulation of binding", "negative regulation of proteolysis", and "negative regulation of peptidase activity" and in the KEGG pathways including "transcriptional misregulation in cancer", "cellular senescence", "apoptosis", "FoxO signaling pathway", "cell cycle", "NF-kappa B signaling pathway", "p53 signaling pathway", "pentose phosphate pathway", and "protein export". For the cell-cell communication network analysis, the different interaction profiles between cell types were detected among primary, metastatic, and recurrent osteosarcomas. Further exploration of the KEGG pathway revealed that these ligand/receptor interactions may be associated with the NF-κB signaling pathway and its interacted mediators. In conclusion, the present study for the first time explored the scRNA-seq dataset in osteosarcoma, and our results revealed the 11 clustered cell types and demonstrated the novel cell-cell interactions among different cell types in primary, metastatic, and recurrent osteosarcomas. The NF-κB signaling pathway may play a key role in regulating the TME of osteosarcoma. The present study may provide new insights into understanding the molecular mechanisms of osteosarcoma pathophysiology.

Re-Irradiation With Stereotactic Body Radiotherapy for In-Field Recurrence of Pancreatic Cancer After Prior Stereotactic Body Radiotherapy: Analysis of 24 Consecutive Cases.

PURPOSE/OBJECTIVES: Locally recurrent pancreatic cancer is a therapeutic challenge, and aggressive approaches are needed to improve its clinical outcomes. Stereotactic body radiotherapy (SBRT) is a promising treatment for pancreatic cancer with an excellent local control and acceptable toxicity. However, the safety and efficacy of SBRT for in-field recurrence after initial SBRT remain unknown. The aim of the study was to investigate the feasibility of re-irradiation with SBRT for locally recurrent pancreatic cancer after prior definitive SBRT. MATERIAL/METHODS: Twenty-four consecutive patients with pancreatic cancer received two courses of SBRT in our center between January 2014 and December 2016. The median prescription dose of the initial and second courses of SBRT was 35.5 Gy/5-7f and 32 Gy/5-8f, respectively. Clinical outcomes including overall survival (OS), disease control, and toxicity were evaluated after treatment. RESULTS: The median interval between two courses of SBRT was 13 months (range: 6-29 months). From the first SBRT, the median OS of 18 patients with limited diseases was 26 months (95% CI: 19.1-32.95 months). The median OS of 12 patients without metastasis was 14 months (95% CI: 10.6-17.4 months) from re-irradiation of SBRT. The overall response rate and disease control rate were 50% and 13%, and 100% and 86.9% after each SBRT, respectively. Carbohydrate antigen 19-9 (CA19-9) levels declined dramatically after re-irradiation within 1 month (p = 0.002) and 3 months (p = 0.028). Twelve (75%) out of 16 patients had pain relief after re-irradiation. None of the patients experienced gastrointestinal toxicity. CONCLUSIONS: Re-irradiation with SBRT can provide favorable outcomes and effective analgesia with mild toxicity after prior SBRT for in-field recurrent pancreatic cancer, which might be feasible for locally relapsed pancreatic cancer.

Personalized designs of adjuvant radiotherapy for pancreatic cancer based on molecular profiles.

This study aims to identify postoperative recurrence patterns of pancreatic cancer with different molecular profiles, which provides evidence for personalized target volumes of adjuvant radiotherapy. Patients with pathologically confirmed resectable pancreatic ductal adenocarcinoma were included. Recurrences were treated with stereotactic body radiation therapy. Immunohistochemical staining of Ki-67, P53, and programmed cell death-ligand 1 (PD-L1) was carried out. Both of the intensities of Ki-67 and P53 were classified as 10% or less, 11%-49%, and 50% or more. Eighty-nine patients had PD-L1 tested, stratified as TC0 and IC0, and TC1/2 or IC1/2. Distances with significant differences among different levels or beyond 10 mm were of interest. With the increasing intensity of Ki-67, the distance from the superior and posterior border of 80% recurrences to the celiac axis (CA) ranged from 10.1 to 13.8 mm and 9.2 to 11.0 mm. The distance from the inferior and posterior border of 80% recurrences to the superior mesenteric artery (SMA) ranged from 9.4 to 9.9 mm and 9.4 to 11.0 mm. Similarly, with the increasing intensity of P53, the distance from the superior and posterior border of 80% recurrences to the CA ranged from 9.7 to 13.2 mm and 10.1 to 10.6 mm. The distance from the inferior and anterior border of 80% recurrences to the SMA ranged from 9.5 to 9.9 mm and 8.6 to 9.4 mm. Regarding the increasing level of PD-L1, the distance from the superior border of 80% recurrences to the CA ranged from 10.9 to 13.5 mm. A biologically effective dose of more than 65 Gy to local recurrences was predictive of favorable outcomes in all levels of Ki-67, P53, and PD-L1. Nonuniform expansions of regions of interest based on different levels of molecular profiles to form target volumes could cover most recurrences, which might be feasible for adjuvant radiotherapy.

Treatment of limb synovial sarcoma with metastasis at presentation.

Limb synovial sarcoma (LSS) patients with metastasis at presentation usually have a very poor prognosis. Little is known about survival prediction and risk factors in these patients owing to the condition's rarity. Thus, this study examined the survival and prognostic variables of metastatic LSS.Clinical data for LSS patients with metastasis at presentation from 1975 to 2016 were obtained from the surveillance, epidemiology, and end results database. The Kaplan-Meier method was used to determine the survival curves. Univariate and multivariate Cox regression analysis were conducted to identify the prognostic predictors.The study enrolled 217 patients. Male predominance was observed in the metastatic LSS group. The median age at diagnosis of this population was 40 years. The subtypes were "not otherwise specified" (49.8%), spindle cell (32.7%), biphasic (17.1%), and epithelioid cell (0.5%). The 3-year overall and cancer-specific survival rates of the entire group were 27.2% and 28.3%, respectively. Tumor size <10 cm, surgery, radiotherapy, and chemotherapy were independent predictors of improved overall and cancer-specific survival in the multivariate analyses.Comprehensive treatment for LSS patients with metastasis at diagnosis is necessary and effective and can prolong survival.

Validation of the eighth edition of the AJCC staging system for patients with pancreatic adenocarcinoma initially receiving chemoradiotherapy and proposal of modifications.

Objective: To validate the eighth edition of the AJCC staging system in patients with pancreatic adenocarcinoma receiving only stereotactic body radiation therapy and chemotherapy, and to propose modifications to improve prognostic accuracy. Methods: Patients with pathologically confirmed pancreatic adenocarcinoma without metastasis who were undergoing only chemoradiotherapy were included and staged according to the seventh and eighth editions of the AJCC staging system. Meanwhile, another group of stage T4 patients from the above enrollment with only portal vein involvement with or without tumor thrombi (PV ± PVTT) were retrieved for survival comparisons. Modifications were proposed according to the survival comparisons. A cohort from the SEER database was used for external validation of the modified staging system. Results: A total of 683 patients were included. Patients with N2 or N1 but different T stages had significantly different survival outcomes according to the eighth edition. The survival of patients with PV ± PVTT was comparable to that of patients with T4 tumors. The concordance index of the seventh and eighth editions, and the modified staging system was 0.744 (95%CI: 0.718-0.769), 0.750 (95%CI: 0.725-0.775), and 0.788 (95%CI: 0.762-0.813), respectively. For external validation, the concordance index was 0.744 (95%CI: 0.718-0.770), 0.750 (95%CI: 0.724-0.776), and 0.788 (95%CI: 0.762-0.814), respectively. Conclusions: The modified staging system is suggested to have the most accurate prognostic value. Hence, PV ± PVTT should be added to the definition of T4 tumors regardless of tumor size. Patients with N2 or N1 in different T stages could be regrouped into different substages. Additionally, stage III should be subclassified into IIIA (T3N2 and T4N0) and IIIB (T4N1-2).

Optical asymmetric cryptosystem for multi-image in cyan-magenta-yellow-black color space.

In this paper, we propose an optical single-channel asymmetric cryptosystem for multi-image in cyan-magenta-yellow-black (CMYK) color space. To the best of our knowledge, this is the first time that multiple images in CMYK color space have been directly encrypted. The proposed optical asymmetric cryptosystem is based on the quick response (QR) encoding process and the designed Fresnel-linear canonical-fractional Fourier transform (FLFT) encryption process. Each FLFT encryption process consists of phase-truncated FLFT and random amplitude phase masks. The proposed cryptosystem without color space conversion can improve the quality of the decrypted images and avoid the loss of information. In addition, by utilizing the QR codes, the cross talk and quality-loss problems can be reduced efficiently. Numerical simulation results demonstrate that the proposed cryptosystem possesses high robustness against various types of attacks, high security for encrypting multiple color images, and fast encryption efficiency. Furthermore, the proposed cryptosystem outperforms the other relevant cryptosystems and can be extended to encrypt multiple color images in a straightforward way.

Patterns of Local Failure After Stereotactic Body Radiation Therapy and Sequential Chemotherapy as Initial Treatment for Pancreatic Cancer: Implications of Target Volume Design.

PURPOSE: To identify patterns of local failure in patients with pancreatic cancer receiving stereotactic body radiation therapy plus chemotherapy as initial treatment, for the optimal design of target volumes encompassing a majority of local recurrences. METHODS AND MATERIALS: Consecutive patients with resectable or borderline resectable but medically inoperable cancer owing to comorbidities and locally advanced pancreatic cancer undergoing stereotactic body radiation therapy and chemotherapy were reviewed. Local recurrences were plotted with respect to the celiac trunk (CT), superior mesenteric artery (SMA), and splenic artery on 1 computed tomographic scan of a template patient. RESULTS: Five hundred and ten patients were included. Median follow-up of the entire group was 21.8 months (range, 3.1-54.9 months). Two hundred and seventeen patients had locoregional recurrences, whereas local and distant progressions were found in 293 patients. One hundred and sixty-nine (33.2%) and 144 (28.2%) patients had recurrences closer to the CT and SMA, respectively, whereas both invasions of the CT and SMA were found in 115 patients (22.5%). In addition, 33 patients (6.5%) and 49 patients (9.6%) had recurrences at the hepatic hilum and the splenic artery, respectively. Besides these patterns of failure, 138 patients (27.1%) also experienced retroperitoneal progressions. The mean distance to the CT, SMA, and retroperitoneal recurrence was 9.0, 8.3, and 11.7 mm, respectively. Multivariable analysis demonstrated that advanced pancreatic cancer, recurrences at both the CT and SMA and the hepatic hilum, CA19-9 nonresponders, and BED10 <60 Gy were predictive of worse survival. CONCLUSIONS: Areas closer to the CT, SMA, and retroperitoneal space were at a high risk of local recurrences. Nonuniform and sufficient expansions from the gross tumor volume might be necessary, and the splenic vessels abutting the tumor might also be included in the target volume without compromise of dose constraints of organs at risk. In addition, at least BED10 ≥60 Gy might be required to achieve better outcomes.

Stereotactic Radiation Therapy (SRT) for Brain Metastases of Multiple Primary Tumors: A Single Institution Retrospective Analysis.

Purpose: To evaluate the efficiency and side effects of stereotactic radiation therapy (SRT) with or without other treatments for brain metastases (BM) from various primary tumors. Methods: This was a retrospective analysis of 161 patients with brain metastases treated with SRT. Clinical data, EGFR mutation status and survival data were collected. Follow-up data was analyzed until December 2018. Kaplan-Meier and Cox proportional hazards regression analyses were used for the survival analysis. Results: The median overall survival (OS) was 19 months. No difference was observed in OS between SRT group and SRT + whole brain radiation therapy (WBRT) groups (p = 0.717). Statistically significant factors of better OS after univariable analysis were no extracranial metastases (p = 0.016), BED10-SRT≥50Gy (p = 0.049), oligometastases (1-3 brain metastases) (p < 0.001), GPA score≥2.5 (p = 0.003), RPA class I (p = 0.026), NSCLC tumor type (p = 0.006), targeted therapy (p < 0.001) and controlled extracranial disease (p = 0.011). Multivariate analysis indicated that higher BED10-SRT (≥50Gy, HR = 0.504, p = 0.027), controlled extracranial disease (HR = 0.658, p = 0.039) and targeted therapy (HR = 0.157, <0.001) were independent favorable predictors for OS. Besides that, we also find that the median overall survival (OS) was 22 months in NSCLC patients and controlled extracranial disease (HR = 0.512, p = 0.012) and targeted therapy (HR = 0.168, < 0.001) were independent favorable predictors for OS. Conclusion: For patients with brain metastases, stable extracranial disease, higher BED10-SRT (≥50Gy) and targeted therapy may predict a favorable prognosis.

Health-related quality of life for gemcitabine and nab-paclitaxel plus radiotherapy versus gemcitabine and S-1 plus radiotherapy in patients with metastatic pancreatic cancer.

PURPOSE: To compare the effects of gemcitabine and nab-paclitaxel (GT) plus stereotactic body radiation therapy (SBRT) or gemcitabine and S-1 (GS) plus SBRT on health-related quality of life (HRQOL) of metastatic pancreatic cancer. METHODS: Patients with biopsy-proven and radiographically metastatic pancreatic cancer were included. HRQOL was assessed using the Chinese version of Brief Pain Inventory (BPI) and 5-level European quality of life 5-dimensions (EQ-5D-5L). Data were analyzed with Spearman's rank correlation, ordinal regression, and propensity score-matched analysis. RESULTS: A total of 75 and 89 patients received GT and GS, respectively. The median biological effective dose of GT group and GS group was 59.5 Gy (range 48-85.5 Gy) and 64.4 Gy (range 52.48-85.5 Gy) in 5-8 fractions, respectively. More patients in the GS group had improvement in BPI and EQ-5D-5L compared with those in the GT group (n=38 vs n=15, P<0.001; n=42 vs n=20, P<0.001). No differences of BPI scores were found between pre- and post-treatment in each group, while only the post-treatment EQ-5D-5L score was higher than that at baseline in GS the group (P<0.001). Compared with GS group, it was unlikely for patients receiving GT to have better BPI and EQ-5D-5L. After propensity-matched analysis, more patients in GS group had improvement in BPI and EQ-5D-5L (n=24 vs n=12, P=0.002; n=28 vs n=16, P=0.002). Furthermore, patients with GS had a superior overall survival than those with GT (11.1 months [95% CI: 10.6-11.6 months] vs 9.9 months [95% CI: 8.8-11.0 months]; P=0.005). Both incidences of grade 3 hematological (P=0.024) and gastrointestinal (P=0.049) toxicities were higher in the GT group. CONCLUSION: GS may achieve better HRQOL than GT. Therefore, GS may be an alternative of GT for metastatic pancreatic cancer, especially for Asians.

Integrated Genome-Wide Analysis of Gene Expression and DNA Copy Number Variations Highlights Stem Cell-Related Pathways in Small Cell Esophageal Carcinoma.

Purpose/Objectives. Primary small cell esophageal carcinoma (SCEC) represents a rare and aggressive malignancy without any prospective clinical trial or established treatment strategy at present. Although previous studies have indicated similarities between SCEC and small cell lung cancer (SCLC) in terms of their clinical manifestations, pathology, and morphology, very little genetic information is available on this highly malignant tumor. At present, patients with SCEC are staged and treated according to the guidelines established for SCLC. However, early recurrence and distant metastasis are common, and long-time survivors are rare. Current options available for patients with relapsed SCEC are fairly unsatisfactory, and their prognosis is generally poor. Novel therapeutic approaches against SCEC are therefore urgently needed and require a deeper understanding of the underlying genetic mechanisms. The current investigation aims to characterize the gene expression profile and copy number variations (CNVs) in SCEC to clarify molecular markers and pathways that may possess clinical significance. Materials/Methods. De novo expression array was carried out on three matched sets of primary SCEC and adjacent normal tissue samples procured from the institutional tissue bank, utilizing the Affymetrix HG U133 Plus 2.0 Array. After individual tissue normalization, the statistical software GeneSpring GX 12.5 was used to determine differentially expressed genes (DEGs) in the tumors relative to their paired normal tissues. Gene enrichments in addition to functional annotation and gene interaction networks were performed using DAVID 6.8 and STRING 10.0, respectively. A gene alteration was determined to be recurrent if it was observed in at least 2 samples. Chromosomes X and Y were not included in calculations as gender differences are a known source of analysis bias. The DEGs of at least one SCEC sample could be mapped to the CNV regions (fold change (FC) ≥ 2 and false discovery rate (FDR) < 0.01) after gene expression profiling by RefSeq Transcript ID. These overlapped genes were subjected to the functional annotation using DAVID 6.8. In order to elucidate the effect of CNV on mRNA expression, we integrated the genome-wide copy number data and gene expression in 3 paired samples. CNV-associated gene expression aberration (CNV-FC) was calculated for the recurrent DEGs using previously published integrated microarray data as reference. Pearson's correlation coefficient was employed to determine if there was a statistical correlation between the gene expression log2 ratios and their copy numbers using the SPSS 19.0 software. Genes that possessed CNV-FC ≥ 2 and r ≥ 0.6 (p < 0.05) were determined to be genes potentially associated with cancer. Results. High-quality DNA and total RNA were first extracted from both SCEC and normal tissues. Microarray data showed significant upregulation in WNT gene sets and downregulation in the PTEN and notch gene sets in SCEC. Functional annotation showed that genes associated with DNA replication, mitosis, cell cycle, DNA repair, telomere maintenance, RB, and p53 pathways were significantly altered in SCEC compared to corresponding noncancerous tissues (Benjamini p < 0.05). Thirteen recurrent CNVs were found in all SCEC samples by array CGH. Chromosomal regions with gain were located in 14q11.2, and regions with loss were located in 4q22.3-23.3, 3q25.31-q29, 5p15.31-15.2, 8q21.11-24.3, and 9p23-13.1 in all samples. In two samples, the 14q11.2-32.33 region was amplified, whereas 3p26.3-25.3, 4p16.3-11, 4q11-22.3, 4q23-25, 8p23.3, and 16p13.3 were deleted. We further identified 306 genes that consistently differed in copy number and expression (194 upregulated and 112 downregulated) between the SCEC and noncancerous tissues in all three samples. These genes were significantly enriched with those involved in cell cycle, mitosis, DNA repair, P53 pathway, and RB pathway, according to their functional annotation. These 306 DEGs also included network genes of the above pathways such as NUF2, CCNE2, NFIB, ETV5, KLF5, ATAD2, NDC80, and ZWINT. In addition, 39 individual DEGs demonstrated a minimum 2-fold copy number-associated expression change (median: 5.35, 95% CI: 4.53-16.98) and Pearson's correlation coefficient ≥ 0.6 (p < 0.05), of which PTP4A3 showed the highest correlation (CNV-FC = 21362.13; Pearson's correlation coefficient = 0.9983; p = 0.037). Two distinct groups of genes belonging to each SCEC and nonmalignant tissues were observed upon unsupervised two-way (genes and samples) hierarchical clustering. Conclusions. The current investigation is the first to produce data regarding the genomic signature of SCEC at the transcription level and in relation to CNVs. Our preliminary data indicate possible key roles of WNT and notch signaling in SCEC and overexpressed PTP4A3 as a potential therapeutic target. Further validation of our findings is warranted.